This paper aims to investigate the role of bi-directional shear in the mechanical behaviour of granular materials and macro-micro relations by conducting experiments and discrete element method(DEM)modelling.The bi-di...This paper aims to investigate the role of bi-directional shear in the mechanical behaviour of granular materials and macro-micro relations by conducting experiments and discrete element method(DEM)modelling.The bi-directional shear consists of a static shear consolidation and subsequent shear under constant vertical stress and constant volume conditions.A side wall node loading method is used to exert bi-directional shear of various angles.The results show that bi-directional shear can significantly influence the mechanical behaviour of granular materials.However,the relationship between bidirectional shear and mechanical responses relies on loading conditions,i.e.constant vertical stress or constant volume conditions.The stress states induced by static shear consolidation are affected by loading angles,which are enlarged by subsequent shear,consistent with the relationship between bidirectional shear and principal stresses.It provides evidence for the dissipation of stresses accompanying static liquefaction of granular materials.The presence of bi-directional principal stress rotation(PSR)is demonstrated,which evidences why the bi-directional shear of loading angles with components in two directions results in faster dissipations of stresses with static liquefaction.Contant volume shearing leads to cross-anisotropic stress and fabric at micro-contacts,but constant vertical stress shearing leads to complete anisotropic stress and fabric at micro-contacts.It explains the differentiating relationship between stress-strain responses and fabric anisotropy under these two conditions.Micromechanical signatures such as the slip state of micro-contacts and coordination number are also examined,providing further insights into understanding granular behaviour under bi-directional shear.展开更多
Deep engineering disasters,such as rockbursts and collapses,are more related to the shear slip of rock joints.A novel multifunctional device was developed to study the shear failure mechanism in rocks.Using this devic...Deep engineering disasters,such as rockbursts and collapses,are more related to the shear slip of rock joints.A novel multifunctional device was developed to study the shear failure mechanism in rocks.Using this device,the complete shearedeformation process and long-term shear creep tests could be performed on rocks under constant normal stiffness(CNS)or constant normal loading(CNL)conditions in real-time at high temperature and true-triaxial stress.During the research and development process,five key technologies were successfully broken through:(1)the ability to perform true-triaxial compressioneshear loading tests on rock samples with high stiffness;(2)a shear box with ultra-low friction throughout the entire stress space of the rock sample during loading;(3)a control system capable of maintaining high stress for a long time and responding rapidly to the brittle fracture of a rock sample as well;(4)a refined ability to measure the volumetric deformation of rock samples subjected to true triaxial shearing;and(5)a heating system capable of maintaining uniform heating of the rock sample over a long time.By developing these technologies,loading under high true triaxial stress conditions was realized.The apparatus has a maximum normal stiffness of 1000 GPa/m and a maximum operating temperature of 300C.The differences in the surface temperature of the sample are constant to within5C.Five types of true triaxial shear tests were conducted on homogeneous sandstone to verify that the apparatus has good performance and reliability.The results show that temperature,lateral stress,normal stress and time influence the shear deformation,failure mode and strength of the sandstone.The novel apparatus can be reliably used to conduct true-triaxial shear tests on rocks subjected to high temperatures and stress.展开更多
Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spac...Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spacing influence the near-bed flow structures in a gravel-bed stream.Boulders are staggered over a gravel-bed stream with three different inter-boulder spacing namely(a)large(b)medium and(c)small spacing.An acoustic Doppler velocimeter was used for flow measurements in a rectangular channel and the results were compared with those acquired from numerical simulation.The time-averaged velocity profiles at the near-wake flow zones of boulders experience maximum flow retardation which is an outcome of the boulder-induced form roughness.The ratio of velocity differences associated to form and skin roughness and its positive magnitude reveals the dominance of form roughness closest to the boulders.Form roughness computed is 1.75 to 2 times higher than the skin roughness at the near-wake flow region.In particular,the collective immobile boulders placed at different inter-boulder spacings developed high and low bed shear stresses closest to the boulders.The low bed shear stresses characterised by a secondary peak developed at the trough location of the boulders is attributed to the skin shear stress.Further,the spatial averaging of time-averaged flow quantities gives additional impetus to present an improved illustration of fluid shear stresses.The formation of form-induced shear stress is estimated to be 17%to 23%of doubleaveraged Reynolds shear stress and partially compensates for the damping of time-averaged Reynolds shear stress in the interfacial sub-layer.The quadrant analysis of spatial velocity fluctuations depicts that the form-induced shear stresses are dominant in the interfacial sub-layer and have no significance above the gravel-bed surface.展开更多
Great potential of underground gas/energy storage in salt caverns seems to be a promising solution to support renewable energy.In the underground storage method,the operating cycle unfortunately may reach up to daily ...Great potential of underground gas/energy storage in salt caverns seems to be a promising solution to support renewable energy.In the underground storage method,the operating cycle unfortunately may reach up to daily or even hourly,which generates complicated pressures on the salt cavern.Furthermore,the mechanical behavior of rock salt may change and present distinct failure characteristics under different stress states,which affects the performance of salt cavern during the time period of full service.To reproduce a similar loading condition on the cavern surrounding rock mass,the cyclic triaxial loading/unloading tests are performed on the rock salt to explore the mechanical transition behavior and failure characteristics under different confinement.Experimental results show that the rock salt samples pre-sent a diffused shear failure band with significant bulges at certain locations in low confining pressure conditions(e.g.5 MPa,10 MPa and 15 MPa),which is closely related to crystal misorientation and grain boundary sliding.Under the elevated confinement(e.g.20 MPa,30 MPa and 40 MPa),the dilation band dominates the failure mechanism,where the large-size halite crystals are crushed to be smaller size and new pores are developing.The failure transition mechanism revealed in the paper provides additional insight into the mechanical performance of salt caverns influenced by complicated stress states.展开更多
Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice ...Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.展开更多
Background:Shear stress-induced erythrocyte damage,namely hemolysis,is an important problem in the development of blood-contacting medical devices such as mechanical circulatory support devices.Computational fluid dyn...Background:Shear stress-induced erythrocyte damage,namely hemolysis,is an important problem in the development of blood-contacting medical devices such as mechanical circulatory support devices.Computational fluid dynamics simulation combined with hemolysis prediction models have been widely used to predict hemolysis.With the development of hemolysis prediction models,the new hemolysis prediction model requires more experimental data to verify.In addition,the difference of in vitro blood-shearing device also affect the accuracy of hemolysis prediction.Methods:To address these problems,a new in vitro blood-shearing device(vortex oscillator)was used to further verify the accuracy of the hemolysis prediction models,and to guide the optimal design of blood-contacting medical devices such as mechanical circulatory support devices.Firstly,the flow field information such as wall stress and velocity of the vortex oscillator under different speeds was analyzed.Secondly,different hemolysis prediction models were used to calculate hemolysis,and the predicted data was compared with the experimental data.Results and Conclusion:In this study,the flow field information inside the vortex oscillator at high rotational speeds was systematically investigated,and the prediction of hemolysis was carried out.The results showed that the predicted data of hemolysis was significantly different from the experimental data,which indicated that it was urgent to establish a standardized in vitro blood-shearing platform to provide a reference for accurate hemolysis prediction.展开更多
Conventional numerical solutions developed to describe the geomechanical behavior of rock interfaces subjected to differential load emphasize peak and residual shear strengths.The detailed analysis of preand post-peak...Conventional numerical solutions developed to describe the geomechanical behavior of rock interfaces subjected to differential load emphasize peak and residual shear strengths.The detailed analysis of preand post-peak shear stress-displacement behavior is central to various time-dependent and dynamic rock mechanic problems such as rockbursts and structural instabilities in highly stressed conditions.The complete stress-displacement surface(CSDS)model was developed to describe analytically the pre-and post-peak behavior of rock interfaces under differential loads.Original formulations of the CSDS model required extensive curve-fitting iterations which limited its practical applicability and transparent integration into engineering tools.The present work proposes modifications to the CSDS model aimed at developing a comprehensive and modern calibration protocol to describe the complete shear stressdisplacement behavior of rock interfaces under differential loads.The proposed update to the CSDS model incorporates the concept of mobilized shear strength to enhance the post-peak formulations.Barton’s concepts of joint roughness coefficient(JRC)and joint compressive strength(JCS)are incorporated to facilitate empirical estimations for peak shear stress and normal closure relations.Triaxial/uniaxial compression test and direct shear test results are used to validate the updated model and exemplify the proposed calibration method.The results illustrate that the revised model successfully predicts the post-peak and complete axial stressestrain and shear stressedisplacement curves for rock joints.展开更多
Understanding the mechanical properties of the lithologies is crucial to accurately determine the horizontal stress magnitude.To investigate the correlation between the rock mass properties and maximum horizontal stre...Understanding the mechanical properties of the lithologies is crucial to accurately determine the horizontal stress magnitude.To investigate the correlation between the rock mass properties and maximum horizontal stress,the three-dimensional(3D)stress tensors at 89 measuring points determined using an improved overcoring technique in nine mines in China were adopted,a newly defined characteristic parameter C_(ERP)was proposed as an indicator for evaluating the structural properties of rock masses,and a fuzzy relation matrix was established using the information distribution method.The results indicate that both the vertical stress and horizontal stress exhibit a good linear growth relationship with depth.There is no remarkable correlation between the elastic modulus,Poisson's ratio and depth,and the distribution of data points is scattered and messy.Moreover,there is no obvious relationship between the rock quality designation(RQD)and depth.The maximum horizontal stress σ_(H) is a function of rock properties,showing a certain linear relationship with the C_(ERP)at the same depth.In addition,the overall change trend of σ_(H) determined by the established fuzzy identification method is to increase with the increase of C_(ERP).The fuzzy identification method also demonstrates a relatively detailed local relationship betweenσ_H and C_(ERP),and the predicted curve rises in a fluctuating way,which is in accord well with the measured stress data.展开更多
Determination of Shear Bond strength(SBS)at interlayer of double-layer asphalt concrete is crucial in flexible pavement structures.The study used three Machine Learning(ML)models,including K-Nearest Neighbors(KNN),Ext...Determination of Shear Bond strength(SBS)at interlayer of double-layer asphalt concrete is crucial in flexible pavement structures.The study used three Machine Learning(ML)models,including K-Nearest Neighbors(KNN),Extra Trees(ET),and Light Gradient Boosting Machine(LGBM),to predict SBS based on easily determinable input parameters.Also,the Grid Search technique was employed for hyper-parameter tuning of the ML models,and cross-validation and learning curve analysis were used for training the models.The models were built on a database of 240 experimental results and three input variables:temperature,normal pressure,and tack coat rate.Model validation was performed using three statistical criteria:the coefficient of determination(R2),the Root Mean Square Error(RMSE),and the mean absolute error(MAE).Additionally,SHAP analysis was also used to validate the importance of the input variables in the prediction of the SBS.Results show that these models accurately predict SBS,with LGBM providing outstanding performance.SHAP(Shapley Additive explanation)analysis for LGBM indicates that temperature is the most influential factor on SBS.Consequently,the proposed ML models can quickly and accurately predict SBS between two layers of asphalt concrete,serving practical applications in flexible pavement structure design.展开更多
Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types...Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.展开更多
Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototox...Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing loss.The etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental factors.Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss.Short non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response.Sensory hair cell death is a central histopathological finding in sensorineural hearing loss.As these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing loss.Ovid EMBASE,Ovid MEDLINE,Web of Science Core Collection,and ClinicalTrials.gov databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical trials.Registe red clinical trials known to the senior author we re also assessed.A total of 222studies were thus identified.After excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text screening.This resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review.MiRNAs miR-34a and miR-29b levels increase with age in mice.These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT1p53,and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis.Furthermore,hypoxia and oxidative stress had a similar adve rse apoptotic effect,which was inhibited by resve ratrol and a myocardial inhibitorassociated transcript,a miR-29b competing endogenous mRNA.Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice-an effect that was corrected by inner ear stem cell-derived exosomes.There is ongoing work seeking to determine if these findings can be effectively translated to humans.展开更多
BACKGROUND Revisiting the epidemiology of posttraumatic stress symptoms(PTSSs)among university students during the coronavirus disease 2019(COVID-19)pandemic as well as understanding the mental health help-seeking beh...BACKGROUND Revisiting the epidemiology of posttraumatic stress symptoms(PTSSs)among university students during the coronavirus disease 2019(COVID-19)pandemic as well as understanding the mental health help-seeking behavior of individuals with PTSSs has critical implications for public mental health strategies in future medical pandemics.AIM To investigate the prevalence and correlates of PTSSs among university students during the first wave of the COVID-19 pandemic in China and to examine mental health help-seeking behaviors among these students.METHODS A total of 2507 Chinese university students were recruited via snowball sampling.The students completed the Seven-item Screening Scale for Post-traumatic Stress Disorder during the first wave of the COVID-19 pandemic in China.Sociodemo-graphic characteristics,pandemic-related characteristics,and mental health help-seeking behaviors of students with PTSSs were also collected.RESULTS The prevalence of PTSSs among the participants was 28.0%.Seven significant correlates of PTSSs were identified(odds ratio=1.23-3.65,P≤0.024):Female sex,being 19 years old or older,living with others or alone,a low level of family economic status,fair or poor interpersonal relationships,severe or very severe local pandemic,and having family members diagnosed with COVID-19.However,only 3.28%of the students with PTSSs reported seeking help from mental health specialists.Among the 23 students who sought help from mental health specialists,13 opted for online or telephone-based psychological consultation.CONCLUSION Our data suggest that there was a high risk of PTSSs among university students and a high level of unmet mental health needs during the COVID-19 pandemic.The delivery of mental health services online or via telephone is a promising approach to address these unmet needs.展开更多
BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current statu...BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current status of family rearing,parental stress,and behavioral and emotional problems of preschool children and to analyze the mediating effect of the current status of family rearing on parental stress and behavioral/emo-tional problems.METHODS We use convenience sampling to select 258 preschool children in the physical examination center of our hospital from October 2021 to September 2023.The children and their parents were evaluated using a questionnaire survey.Pearson's correlation was used to analyze the correlation between child behavioral and emotional problems and parental stress and family rearing,and the structural equation model was constructed to test the mediating effect.RESULTS The score for behavioral/emotional problems of 258 preschool children was(27.54±3.63),the score for parental stress was(87.64±11.34),and the score for parental family rearing was(31.54±5.24).There was a positive correlation between the behavioral and emotional problems of the children and the“hostile/mandatory”parenting style;meanwhile,showed a negative correlation with the“support/participation”parenting style(all P<0.05).The intermediary effect value between the family upbringing of parents in parental stress and children's behavior problems was 29.89%.CONCLUSION Parental family upbringing has a mediating effect between parental stress and behavioral and emotional problems of children.Despite paying attention to the behavioral and emotional problems of preschool-age children,clinical medical staff should provide correct and reasonable parenting advice to their parents to promote the mental health of preschool-age children.展开更多
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with...Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder.In addition,the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment.Evidence suggests that this condition is a multisystem disorder that affects many biological systems,raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder.We performed a PubMed search for microRNAs(miRNAs)in post-traumatic stress disorder(PTSD)that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023.These included four studies with whole blood,seven with peripheral blood mononuclear cells,four with plasma extracellular vesicles/exosomes,and one with serum exosomes.One of these studies had also used whole plasma.Two studies were excluded as they did not involve microRNA biomarkers.Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat,and only two were from recently traumatized adult subjects.In measuring miRNA expression levels,many of the studies had used microarray miRNA analysis,miRNA Seq analysis,or NanoString panels.Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls.The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR-3130-5p in whole blood;miR-193a-5p,-7113-5p,-125a,-181c,and-671-5p in peripheral blood mononuclear cells;miR-10b-5p,-203a-3p,-4488,-502-3p,-874-3p,-5100,and-7641 in plasma extracellular vesicles/exosomes;and miR-18a-3p and-7-1-5p in blood plasma.Several important limitations identified in the studies need to be taken into account in future studies.Further studies are warranted with war veterans and recently traumatized children,adolescents,and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs.展开更多
Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals an...Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.展开更多
The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
Hemodynamic parameters play an important role in aneurysm formation and growth. However, it is difficult to directly observe a rapidly growing de novo aneurysm in a patient. To investigate possible associations betwee...Hemodynamic parameters play an important role in aneurysm formation and growth. However, it is difficult to directly observe a rapidly growing de novo aneurysm in a patient. To investigate possible associations between hemodynamic parameters and the formation and growth of intracranial aneurysms, the present study constructed a computational model of a case with an internal carotid artery aneurysm and an anterior communicating artery aneurysm, based on the CT angiography findings of a patient. To simulate the formation of the anterior communicating artery aneurysm and the growth of the internal carotid artery aneurysm, we then constructed a model that virtually removed the anterior communicating artery aneurysm, and a further two models that also progressively decreased the size of the internal carotid artery aneurysm. Computational simulations of the fluid dynamics of the four models were performed under pulsatile flow conditions, and wall shear stress was compared among the different models. In the three aneurysm growth models, increasing size of the aneurysm was associated with an increased area of low wall shear stress, a significant decrease in wall shear stress at the dome of the aneurysm, and a significant change in the wall shear stress of the parent artery. The wall shear stress of the anterior communicating artery remained low, and was significantly lower than the wall shear stress at the bifurcation of the internal carotid artery or the bifurcation of the middle cerebral artery. After formation of the anterior communicating artery aneurysm, the wall shear stress at the dome of the internal carotid artery aneurysm increased significantly, and the wall shear stress in the upstream arteries also changed significantly. These findings indicate that low wall shear stress may be associated with the initiation and growth of aneurysms, and that aneurysm formation and growth may influence hemodynamic parameters in the local and adjacent arteries.展开更多
In presence of difficult conditions in coal mining roadways, an adequate stabilization of the excavation boundary is required to ensure a safe progress of the construction. The stabilization of the roadways can be imp...In presence of difficult conditions in coal mining roadways, an adequate stabilization of the excavation boundary is required to ensure a safe progress of the construction. The stabilization of the roadways can be improved by fully grouted rock bolt, offering properties optimal to the purpose and versatility in use. Investigations of load transfer between the bolt and grout indicate that the bolt profile shape and spacing play an important role in improving the shear strength between the bolt and the surrounding strata. This study proposes a new analytical solution for calculation displacement and shear stress in a fully encapsulated rock bolt in jointed rocks. The main characteristics of the analytical solution consider the bolt profile and jump plane under pull test conditions. The performance of the proposed analytical solution, for three types of different bolt profile configurations, is validated by ANSYS software. The results show there is a good agreement between analytical and numerical methods. Studies indicate that the rate of displacement and shear stress from the bolt to the rock exponentially decayed. This exponential reduction in displacement and shear stress are dependent on the bolt characteristics such as: rib height, rib spacing, rib width and grout thickness, material and joint properties.展开更多
On the basis of the measurement data pertaining to waves, current, and sediment in February 2012 in the mouth bar of the Modaomen Estuary, the Soulsby formulae with an iterative method are applied to calculating botto...On the basis of the measurement data pertaining to waves, current, and sediment in February 2012 in the mouth bar of the Modaomen Estuary, the Soulsby formulae with an iterative method are applied to calculating bottom shear stresses (BSS) and their effect on a sediment resuspension. Swell induced BSS have been found to be the most important part of the BSS. In this study, the correlation coefficient between a wavecurrent shear stress and SSC is 0.86, and that between current shear stresses and SSC is only 0.40. The peaks of the SSC are consistent with the height and the BSS of the swell. The swell is the main mechanism for the sediment re-suspension, and the tidal current effect on sediment re-suspension is small. The peaks of the SSC are centered on the high tidal level, and the flood tide enhances the wave shear stresses and the SSC near the bottom. The critical shear stress for sediment re-suspension at the observation station is between 0.20 and 0.30 N/m2. Tidal currents are too weak to stir up the bottom sediment into the flow, but a WCI (wave-current interaction) is strong enough to re-suspend the coarse sediment.展开更多
基金the funding support from National Natural Science Foundation of China(Grant No.42307243)Henan Province Science and Technology Research Project(Grant No.232102321102)Shanxi Provincial Key Research and Development Project(Grant No.202102090301009).
文摘This paper aims to investigate the role of bi-directional shear in the mechanical behaviour of granular materials and macro-micro relations by conducting experiments and discrete element method(DEM)modelling.The bi-directional shear consists of a static shear consolidation and subsequent shear under constant vertical stress and constant volume conditions.A side wall node loading method is used to exert bi-directional shear of various angles.The results show that bi-directional shear can significantly influence the mechanical behaviour of granular materials.However,the relationship between bidirectional shear and mechanical responses relies on loading conditions,i.e.constant vertical stress or constant volume conditions.The stress states induced by static shear consolidation are affected by loading angles,which are enlarged by subsequent shear,consistent with the relationship between bidirectional shear and principal stresses.It provides evidence for the dissipation of stresses accompanying static liquefaction of granular materials.The presence of bi-directional principal stress rotation(PSR)is demonstrated,which evidences why the bi-directional shear of loading angles with components in two directions results in faster dissipations of stresses with static liquefaction.Contant volume shearing leads to cross-anisotropic stress and fabric at micro-contacts,but constant vertical stress shearing leads to complete anisotropic stress and fabric at micro-contacts.It explains the differentiating relationship between stress-strain responses and fabric anisotropy under these two conditions.Micromechanical signatures such as the slip state of micro-contacts and coordination number are also examined,providing further insights into understanding granular behaviour under bi-directional shear.
基金financial support from the National Natural Science Foundation of China(Grant Nos.52209125 and 51839003).
文摘Deep engineering disasters,such as rockbursts and collapses,are more related to the shear slip of rock joints.A novel multifunctional device was developed to study the shear failure mechanism in rocks.Using this device,the complete shearedeformation process and long-term shear creep tests could be performed on rocks under constant normal stiffness(CNS)or constant normal loading(CNL)conditions in real-time at high temperature and true-triaxial stress.During the research and development process,five key technologies were successfully broken through:(1)the ability to perform true-triaxial compressioneshear loading tests on rock samples with high stiffness;(2)a shear box with ultra-low friction throughout the entire stress space of the rock sample during loading;(3)a control system capable of maintaining high stress for a long time and responding rapidly to the brittle fracture of a rock sample as well;(4)a refined ability to measure the volumetric deformation of rock samples subjected to true triaxial shearing;and(5)a heating system capable of maintaining uniform heating of the rock sample over a long time.By developing these technologies,loading under high true triaxial stress conditions was realized.The apparatus has a maximum normal stiffness of 1000 GPa/m and a maximum operating temperature of 300C.The differences in the surface temperature of the sample are constant to within5C.Five types of true triaxial shear tests were conducted on homogeneous sandstone to verify that the apparatus has good performance and reliability.The results show that temperature,lateral stress,normal stress and time influence the shear deformation,failure mode and strength of the sandstone.The novel apparatus can be reliably used to conduct true-triaxial shear tests on rocks subjected to high temperatures and stress.
文摘Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spacing influence the near-bed flow structures in a gravel-bed stream.Boulders are staggered over a gravel-bed stream with three different inter-boulder spacing namely(a)large(b)medium and(c)small spacing.An acoustic Doppler velocimeter was used for flow measurements in a rectangular channel and the results were compared with those acquired from numerical simulation.The time-averaged velocity profiles at the near-wake flow zones of boulders experience maximum flow retardation which is an outcome of the boulder-induced form roughness.The ratio of velocity differences associated to form and skin roughness and its positive magnitude reveals the dominance of form roughness closest to the boulders.Form roughness computed is 1.75 to 2 times higher than the skin roughness at the near-wake flow region.In particular,the collective immobile boulders placed at different inter-boulder spacings developed high and low bed shear stresses closest to the boulders.The low bed shear stresses characterised by a secondary peak developed at the trough location of the boulders is attributed to the skin shear stress.Further,the spatial averaging of time-averaged flow quantities gives additional impetus to present an improved illustration of fluid shear stresses.The formation of form-induced shear stress is estimated to be 17%to 23%of doubleaveraged Reynolds shear stress and partially compensates for the damping of time-averaged Reynolds shear stress in the interfacial sub-layer.The quadrant analysis of spatial velocity fluctuations depicts that the form-induced shear stresses are dominant in the interfacial sub-layer and have no significance above the gravel-bed surface.
基金This research was financially supported by the Science and Technology Department of Sichuan Province Project,China(Grant Nos.2022YFSY0007,2021YFH0010)the National Scientific Science Foundation of China(Grant No.U20A20266).
文摘Great potential of underground gas/energy storage in salt caverns seems to be a promising solution to support renewable energy.In the underground storage method,the operating cycle unfortunately may reach up to daily or even hourly,which generates complicated pressures on the salt cavern.Furthermore,the mechanical behavior of rock salt may change and present distinct failure characteristics under different stress states,which affects the performance of salt cavern during the time period of full service.To reproduce a similar loading condition on the cavern surrounding rock mass,the cyclic triaxial loading/unloading tests are performed on the rock salt to explore the mechanical transition behavior and failure characteristics under different confinement.Experimental results show that the rock salt samples pre-sent a diffused shear failure band with significant bulges at certain locations in low confining pressure conditions(e.g.5 MPa,10 MPa and 15 MPa),which is closely related to crystal misorientation and grain boundary sliding.Under the elevated confinement(e.g.20 MPa,30 MPa and 40 MPa),the dilation band dominates the failure mechanism,where the large-size halite crystals are crushed to be smaller size and new pores are developing.The failure transition mechanism revealed in the paper provides additional insight into the mechanical performance of salt caverns influenced by complicated stress states.
基金supported financially by the National Natural Science Foundation of China,No.82071272(to YZ).
文摘Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.
基金supported by 2023 Kunshan Science and Technology Association youth science and technology talent lifting project(Project name:Mechanism study of mechanical damage of coagulation factor VWF based on in vitro blood-shearing experimental platform).
文摘Background:Shear stress-induced erythrocyte damage,namely hemolysis,is an important problem in the development of blood-contacting medical devices such as mechanical circulatory support devices.Computational fluid dynamics simulation combined with hemolysis prediction models have been widely used to predict hemolysis.With the development of hemolysis prediction models,the new hemolysis prediction model requires more experimental data to verify.In addition,the difference of in vitro blood-shearing device also affect the accuracy of hemolysis prediction.Methods:To address these problems,a new in vitro blood-shearing device(vortex oscillator)was used to further verify the accuracy of the hemolysis prediction models,and to guide the optimal design of blood-contacting medical devices such as mechanical circulatory support devices.Firstly,the flow field information such as wall stress and velocity of the vortex oscillator under different speeds was analyzed.Secondly,different hemolysis prediction models were used to calculate hemolysis,and the predicted data was compared with the experimental data.Results and Conclusion:In this study,the flow field information inside the vortex oscillator at high rotational speeds was systematically investigated,and the prediction of hemolysis was carried out.The results showed that the predicted data of hemolysis was significantly different from the experimental data,which indicated that it was urgent to establish a standardized in vitro blood-shearing platform to provide a reference for accurate hemolysis prediction.
基金The authors acknowledge the financial support from Natural Sciences and Engineering Research Council of Canada through its Discovery Grant program(RGPIN-2022-03893)École de Technologie Supérieure(ÉTS)construction engineering research funding.
文摘Conventional numerical solutions developed to describe the geomechanical behavior of rock interfaces subjected to differential load emphasize peak and residual shear strengths.The detailed analysis of preand post-peak shear stress-displacement behavior is central to various time-dependent and dynamic rock mechanic problems such as rockbursts and structural instabilities in highly stressed conditions.The complete stress-displacement surface(CSDS)model was developed to describe analytically the pre-and post-peak behavior of rock interfaces under differential loads.Original formulations of the CSDS model required extensive curve-fitting iterations which limited its practical applicability and transparent integration into engineering tools.The present work proposes modifications to the CSDS model aimed at developing a comprehensive and modern calibration protocol to describe the complete shear stressdisplacement behavior of rock interfaces under differential loads.The proposed update to the CSDS model incorporates the concept of mobilized shear strength to enhance the post-peak formulations.Barton’s concepts of joint roughness coefficient(JRC)and joint compressive strength(JCS)are incorporated to facilitate empirical estimations for peak shear stress and normal closure relations.Triaxial/uniaxial compression test and direct shear test results are used to validate the updated model and exemplify the proposed calibration method.The results illustrate that the revised model successfully predicts the post-peak and complete axial stressestrain and shear stressedisplacement curves for rock joints.
基金financially supported by the National Natural Science Foundation of China(No.52204084)the Open Research Fund of the State Key Laboratory of Coal Resources and safe Mining,CUMT,China(No.SKLCRSM 23KF004)+3 种基金the Interdisciplinary Research Project for Young Teachers of USTB(Fundamental Research Funds for the Central Universities),China(No.FRF-IDRY-GD22-002)the Fundamental Research Funds for the Central Universities and the Youth Teacher International Exchange and Growth Program,China(No.QNXM20220009)the National Key R&D Program of China(Nos.2022YFC2905600 and 2022 YFC3004601)the Science,Technology&Innovation Project of Xiongan New Area,China(No.2023XAGG0061)。
文摘Understanding the mechanical properties of the lithologies is crucial to accurately determine the horizontal stress magnitude.To investigate the correlation between the rock mass properties and maximum horizontal stress,the three-dimensional(3D)stress tensors at 89 measuring points determined using an improved overcoring technique in nine mines in China were adopted,a newly defined characteristic parameter C_(ERP)was proposed as an indicator for evaluating the structural properties of rock masses,and a fuzzy relation matrix was established using the information distribution method.The results indicate that both the vertical stress and horizontal stress exhibit a good linear growth relationship with depth.There is no remarkable correlation between the elastic modulus,Poisson's ratio and depth,and the distribution of data points is scattered and messy.Moreover,there is no obvious relationship between the rock quality designation(RQD)and depth.The maximum horizontal stress σ_(H) is a function of rock properties,showing a certain linear relationship with the C_(ERP)at the same depth.In addition,the overall change trend of σ_(H) determined by the established fuzzy identification method is to increase with the increase of C_(ERP).The fuzzy identification method also demonstrates a relatively detailed local relationship betweenσ_H and C_(ERP),and the predicted curve rises in a fluctuating way,which is in accord well with the measured stress data.
基金the University of Transport Technology under grant number DTTD2022-12.
文摘Determination of Shear Bond strength(SBS)at interlayer of double-layer asphalt concrete is crucial in flexible pavement structures.The study used three Machine Learning(ML)models,including K-Nearest Neighbors(KNN),Extra Trees(ET),and Light Gradient Boosting Machine(LGBM),to predict SBS based on easily determinable input parameters.Also,the Grid Search technique was employed for hyper-parameter tuning of the ML models,and cross-validation and learning curve analysis were used for training the models.The models were built on a database of 240 experimental results and three input variables:temperature,normal pressure,and tack coat rate.Model validation was performed using three statistical criteria:the coefficient of determination(R2),the Root Mean Square Error(RMSE),and the mean absolute error(MAE).Additionally,SHAP analysis was also used to validate the importance of the input variables in the prediction of the SBS.Results show that these models accurately predict SBS,with LGBM providing outstanding performance.SHAP(Shapley Additive explanation)analysis for LGBM indicates that temperature is the most influential factor on SBS.Consequently,the proposed ML models can quickly and accurately predict SBS between two layers of asphalt concrete,serving practical applications in flexible pavement structure design.
基金supported by the STI 2030—Major Projects 2021ZD0204000,No.2021ZD0204003 (to XZ)the National Natural Science Foundation of China,Nos.32170973 (to XZ),32071018 (to ZH)。
文摘Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.
文摘Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing loss.The etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental factors.Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss.Short non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response.Sensory hair cell death is a central histopathological finding in sensorineural hearing loss.As these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing loss.Ovid EMBASE,Ovid MEDLINE,Web of Science Core Collection,and ClinicalTrials.gov databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical trials.Registe red clinical trials known to the senior author we re also assessed.A total of 222studies were thus identified.After excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text screening.This resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review.MiRNAs miR-34a and miR-29b levels increase with age in mice.These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT1p53,and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis.Furthermore,hypoxia and oxidative stress had a similar adve rse apoptotic effect,which was inhibited by resve ratrol and a myocardial inhibitorassociated transcript,a miR-29b competing endogenous mRNA.Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice-an effect that was corrected by inner ear stem cell-derived exosomes.There is ongoing work seeking to determine if these findings can be effectively translated to humans.
文摘BACKGROUND Revisiting the epidemiology of posttraumatic stress symptoms(PTSSs)among university students during the coronavirus disease 2019(COVID-19)pandemic as well as understanding the mental health help-seeking behavior of individuals with PTSSs has critical implications for public mental health strategies in future medical pandemics.AIM To investigate the prevalence and correlates of PTSSs among university students during the first wave of the COVID-19 pandemic in China and to examine mental health help-seeking behaviors among these students.METHODS A total of 2507 Chinese university students were recruited via snowball sampling.The students completed the Seven-item Screening Scale for Post-traumatic Stress Disorder during the first wave of the COVID-19 pandemic in China.Sociodemo-graphic characteristics,pandemic-related characteristics,and mental health help-seeking behaviors of students with PTSSs were also collected.RESULTS The prevalence of PTSSs among the participants was 28.0%.Seven significant correlates of PTSSs were identified(odds ratio=1.23-3.65,P≤0.024):Female sex,being 19 years old or older,living with others or alone,a low level of family economic status,fair or poor interpersonal relationships,severe or very severe local pandemic,and having family members diagnosed with COVID-19.However,only 3.28%of the students with PTSSs reported seeking help from mental health specialists.Among the 23 students who sought help from mental health specialists,13 opted for online or telephone-based psychological consultation.CONCLUSION Our data suggest that there was a high risk of PTSSs among university students and a high level of unmet mental health needs during the COVID-19 pandemic.The delivery of mental health services online or via telephone is a promising approach to address these unmet needs.
基金Supported by the Shijiazhuang Science and Technology Research and Development Program,No.221460383.
文摘BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current status of family rearing,parental stress,and behavioral and emotional problems of preschool children and to analyze the mediating effect of the current status of family rearing on parental stress and behavioral/emo-tional problems.METHODS We use convenience sampling to select 258 preschool children in the physical examination center of our hospital from October 2021 to September 2023.The children and their parents were evaluated using a questionnaire survey.Pearson's correlation was used to analyze the correlation between child behavioral and emotional problems and parental stress and family rearing,and the structural equation model was constructed to test the mediating effect.RESULTS The score for behavioral/emotional problems of 258 preschool children was(27.54±3.63),the score for parental stress was(87.64±11.34),and the score for parental family rearing was(31.54±5.24).There was a positive correlation between the behavioral and emotional problems of the children and the“hostile/mandatory”parenting style;meanwhile,showed a negative correlation with the“support/participation”parenting style(all P<0.05).The intermediary effect value between the family upbringing of parents in parental stress and children's behavior problems was 29.89%.CONCLUSION Parental family upbringing has a mediating effect between parental stress and behavioral and emotional problems of children.Despite paying attention to the behavioral and emotional problems of preschool-age children,clinical medical staff should provide correct and reasonable parenting advice to their parents to promote the mental health of preschool-age children.
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
文摘Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder.In addition,the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment.Evidence suggests that this condition is a multisystem disorder that affects many biological systems,raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder.We performed a PubMed search for microRNAs(miRNAs)in post-traumatic stress disorder(PTSD)that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023.These included four studies with whole blood,seven with peripheral blood mononuclear cells,four with plasma extracellular vesicles/exosomes,and one with serum exosomes.One of these studies had also used whole plasma.Two studies were excluded as they did not involve microRNA biomarkers.Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat,and only two were from recently traumatized adult subjects.In measuring miRNA expression levels,many of the studies had used microarray miRNA analysis,miRNA Seq analysis,or NanoString panels.Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls.The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR-3130-5p in whole blood;miR-193a-5p,-7113-5p,-125a,-181c,and-671-5p in peripheral blood mononuclear cells;miR-10b-5p,-203a-3p,-4488,-502-3p,-874-3p,-5100,and-7641 in plasma extracellular vesicles/exosomes;and miR-18a-3p and-7-1-5p in blood plasma.Several important limitations identified in the studies need to be taken into account in future studies.Further studies are warranted with war veterans and recently traumatized children,adolescents,and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs.
基金Supported by American Diabetes AssociationAmerican Heart Association+3 种基金NIH NIEHSNIH NIANIH NINDSand NIH ARRA.
文摘Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金supported by the National Natural Science Foundation of China, No. 81171109
文摘Hemodynamic parameters play an important role in aneurysm formation and growth. However, it is difficult to directly observe a rapidly growing de novo aneurysm in a patient. To investigate possible associations between hemodynamic parameters and the formation and growth of intracranial aneurysms, the present study constructed a computational model of a case with an internal carotid artery aneurysm and an anterior communicating artery aneurysm, based on the CT angiography findings of a patient. To simulate the formation of the anterior communicating artery aneurysm and the growth of the internal carotid artery aneurysm, we then constructed a model that virtually removed the anterior communicating artery aneurysm, and a further two models that also progressively decreased the size of the internal carotid artery aneurysm. Computational simulations of the fluid dynamics of the four models were performed under pulsatile flow conditions, and wall shear stress was compared among the different models. In the three aneurysm growth models, increasing size of the aneurysm was associated with an increased area of low wall shear stress, a significant decrease in wall shear stress at the dome of the aneurysm, and a significant change in the wall shear stress of the parent artery. The wall shear stress of the anterior communicating artery remained low, and was significantly lower than the wall shear stress at the bifurcation of the internal carotid artery or the bifurcation of the middle cerebral artery. After formation of the anterior communicating artery aneurysm, the wall shear stress at the dome of the internal carotid artery aneurysm increased significantly, and the wall shear stress in the upstream arteries also changed significantly. These findings indicate that low wall shear stress may be associated with the initiation and growth of aneurysms, and that aneurysm formation and growth may influence hemodynamic parameters in the local and adjacent arteries.
文摘In presence of difficult conditions in coal mining roadways, an adequate stabilization of the excavation boundary is required to ensure a safe progress of the construction. The stabilization of the roadways can be improved by fully grouted rock bolt, offering properties optimal to the purpose and versatility in use. Investigations of load transfer between the bolt and grout indicate that the bolt profile shape and spacing play an important role in improving the shear strength between the bolt and the surrounding strata. This study proposes a new analytical solution for calculation displacement and shear stress in a fully encapsulated rock bolt in jointed rocks. The main characteristics of the analytical solution consider the bolt profile and jump plane under pull test conditions. The performance of the proposed analytical solution, for three types of different bolt profile configurations, is validated by ANSYS software. The results show there is a good agreement between analytical and numerical methods. Studies indicate that the rate of displacement and shear stress from the bolt to the rock exponentially decayed. This exponential reduction in displacement and shear stress are dependent on the bolt characteristics such as: rib height, rib spacing, rib width and grout thickness, material and joint properties.
基金The Program of International S&T Cooperation under contract No.2010DFA24470the National Science Foundation of China under contract No.41376101the Guangdong Provincial Science and Technology Planning Project under contract Nos 2012A030200002 and 2011B031100008
文摘On the basis of the measurement data pertaining to waves, current, and sediment in February 2012 in the mouth bar of the Modaomen Estuary, the Soulsby formulae with an iterative method are applied to calculating bottom shear stresses (BSS) and their effect on a sediment resuspension. Swell induced BSS have been found to be the most important part of the BSS. In this study, the correlation coefficient between a wavecurrent shear stress and SSC is 0.86, and that between current shear stresses and SSC is only 0.40. The peaks of the SSC are consistent with the height and the BSS of the swell. The swell is the main mechanism for the sediment re-suspension, and the tidal current effect on sediment re-suspension is small. The peaks of the SSC are centered on the high tidal level, and the flood tide enhances the wave shear stresses and the SSC near the bottom. The critical shear stress for sediment re-suspension at the observation station is between 0.20 and 0.30 N/m2. Tidal currents are too weak to stir up the bottom sediment into the flow, but a WCI (wave-current interaction) is strong enough to re-suspend the coarse sediment.